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Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice
John D. Belcher, … , Robert P. Hebbel,, Gregory M. Vercellotti
John D. Belcher, … , Robert P. Hebbel,, Gregory M. Vercellotti
Published March 1, 2006
Citation Information: J Clin Invest. 2006;116(3):808-816. https://doi.org/10.1172/JCI26857.
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Research Article Hematology

Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice

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Abstract

Transgenic sickle mice expressing βS hemoglobin have activated vascular endothelium that exhibits enhanced expression of NF-κB and adhesion molecules that promote vascular stasis in sickle, but not in normal, mice in response to hypoxia/reoxygenation. Sickle mice hemolyze rbcs in vivo as demonstrated by increased reticulocyte counts, plasma hemoglobin and bilirubin, and reduced plasma haptoglobin. The heme content is elevated in sickle organs, which promotes vascular inflammation and heme oxygenase-1 expression. Treatment of sickle mice with hemin further increases heme oxygenase-1 expression and inhibits hypoxia/reoxygenation–induced stasis, leukocyte-endothelium interactions, and NF-κB, VCAM-1, and ICAM-1 expression. Heme oxygenase inhibition by tin protoporphyrin exacerbates stasis in sickle mice. Furthermore, treatment of sickle mice with the heme oxygenase enzymatic product carbon monoxide or biliverdin inhibits stasis and NF-κB, VCAM-1, and ICAM-1 expression. Local administration of heme oxygenase-1 adenovirus to subcutaneous skin increases heme oxygenase-1 and inhibits hypoxia/reoxygenation–induced stasis in the skin of sickle mice. Heme oxygenase-1 plays a vital role in the inhibition of vaso-occlusion in transgenic sickle mice.

Authors

John D. Belcher, Hemachandra Mahaseth, Thomas E. Welch, Leo E. Otterbein, Robert P. Hebbel,, Gregory M. Vercellotti

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Figure 1

HO-1 expression is elevated in the organs of sickle mice.

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HO-1 expression is elevated in the organs of sickle mice.
Western blots ...
Western blots for HO-1 were performed on organ homogenates (1 μg of organ DNA per lane) from lungs, livers, and spleens of untreated normal, S+S-Antilles, and BERK mice. (A) The 32-kDa HO-1 bands are shown for each organ and each mouse. (B) The mean HO-1 band intensities (n = 4) ± SD are expressed as a percentage of those in normal control mice. *P < 0.05, normal versus sickle.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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